Characterization of Hepatitis B Virus Infection and Viral DNA Integration in Non-Hodgkin Lymphoma

Background: Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the sero-epidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Methods: The association of HBV infection and NHL was confirmed in a case-control study involving 411 NHL patients and 957 healthy controls from Shanghai, China. The presence of HBV genes and antigens in NHL tissues were detected by PCR and immunohistochemistry. HBV integration was identified by a high-throughput capture sequencing method. Findings: The positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg, and HBV DNA were detected in 34.4% (32/93), 45.2% (42/93), and 47.0% (55/117) NHL tissues, respectively. Furthermore, integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10, and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4 , EGFLAM, MAN1C1, XKR6, ZBTB38, and CCDC91) showed the significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Interpretation: HBV integration is a common event in NHL cells. Further study on the biological consequence of such integration may help to understand the mechanism underling the association of HBV infection and NHL. Funding Statement: This study was funded by grants from the National Key Projects Specialized in Infectious Diseases (2017ZX10201201-008-003), the National Key R&D Program of China (2017YFC0908103, 2017YFC0908104), the National Natural Science Foundation of China (81872505, 81572312), Chinese State Key Laboratory of Oncogenes and Related Genes (91-14-16, 91-15-06), and the Fourth Round of Three-year Public Health Program and Key Disciplines (15GWZK0801).Declaration of Interests: The authors declare that they have no competing interests.Ethics Approval Statement: The study was approved by the institutional ethics review committee of Renji Hospital, Shanghai Jiao-Tong University School of Medicine and conducted according to the principles of the Declaration of Helsinki. Informed consent was obtained from all patients.